2007
DOI: 10.1038/nsmb1235
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Abstract: Proprotein convertase subtilisin kexin type 9 (PCSK9) lowers the abundance of surface low-density lipoprotein (LDL) receptor through an undefined mechanism. The structure of human PCSK9 shows the subtilisin-like catalytic site blocked by the prodomain in a noncovalent complex and inaccessible to exogenous ligands, and that the C-terminal domain has a novel fold. Biosensor studies show that PCSK9 binds the extracellular domain of LDL receptor with K(d) = 170 nM at the neutral pH of plasma, but with a K(d) as lo… Show more

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Cited by 384 publications
(501 citation statements)
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“…The structure of PCSK9 at neutral pH has now been reported by two groups, and raises many intriguing new questions about PCSK9 biochemistry and function [29,31]. The two most striking features of the structure are (i) the catalytic site of the enzyme is blocked by the prodomain in a non-covalent complex ( Figure 5A), and (ii) the C-terminal domain, which consists of three beta-domain modules related to one another by a pseudo three-fold axis, displays a surface rich in histidine residues along a stripe derived primarily from the second module ( Figure 5B).…”
Section: Pcsk9 Structurementioning
confidence: 92%
See 2 more Smart Citations
“…The structure of PCSK9 at neutral pH has now been reported by two groups, and raises many intriguing new questions about PCSK9 biochemistry and function [29,31]. The two most striking features of the structure are (i) the catalytic site of the enzyme is blocked by the prodomain in a non-covalent complex ( Figure 5A), and (ii) the C-terminal domain, which consists of three beta-domain modules related to one another by a pseudo three-fold axis, displays a surface rich in histidine residues along a stripe derived primarily from the second module ( Figure 5B).…”
Section: Pcsk9 Structurementioning
confidence: 92%
“…Biochemical studies using recombinant proteins have revealed that the first EGF-like repeat of the LDLR (EGF-A) suffices for binding of recombinant, purified PCSK9, and that binding to this repeat is calcium dependent [26]. Additionally, the affinity of PCSK9 for the receptor is enhanced at endosomal pH [26,29]. Moreover, mutations associated with PCSK9 gain of function result in enhanced LDLR clearance from the cell surface [28,30], and at least one mutant, D374Y, exhibits ~25-fold increased affinity for the receptor at neutral pH [28,29].…”
Section: Pcsk9 Structurementioning
confidence: 99%
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“…The structure of CHRD is organized in three Cys/His‐rich modules, termed M1, M2 and M3 53, 54. PCSK9 is synthesized as a zymogen and, in the ER, it undergoes autocatalytic cleavage, the latter process being required for PCSK9 maturation and secretion 55.…”
Section: Pcsk9 and Lipoprotein Receptorsmentioning
confidence: 99%
“…4 Mature PCSK9 is secreted from the cell into circulation. [5][6][7][8] The circulating PCSK9 can bind to LDLR, leading to the co-internalization, followed by the degradation of LDLR. 9 Studies demonstrated that the overexpression of PCSK9 results in depletion of LDLR, and thus a dramatic increase in plasma level of cholesterol.…”
Section: Introductionmentioning
confidence: 99%